Preconception phthalate exposure and offspring outcomes

内分泌干扰物(EDs)是一组能够改变正常内分泌的分子 在动物和人类身上发挥作用。我们和其他人已经证明，在宫内暴露于 EDS会导致后代肥胖和血糖稳态异常。邻苯二甲酸酯是一种 在各种工业应用中使用的一组重要的ED，导致 人类常见的暴露风险。一种主要的邻苯二甲酸酯是邻苯二甲酸二(2-乙基己基)-邻苯二甲酸酯(DEHP)，a 广泛使用的化合物，可能存在膳食暴露(食品加工、包装) 是普通人群的主要污染源。无论是人还是动物 模型显示，邻苯二甲酸盐暴露与肥胖的发展和 代谢综合征。与这些研究类似，我们的初步数据显示，接触DEHP 在怀孕和哺乳前和期间通过生理上相关剂量的饮食 改变胎肝DNA甲基化，增加成年后代体重 举止。越来越明显的是，概念化阶段也代表着 子代对环境暴露的易感性窗口。虽然这些机制 负责将代谢性记忆从卵母细胞转移到后代的工作仍有待研究 阐明，两种可能的可能性是表观遗传失调和线粒体异常。 此外，我们和其他人已经证明了表观遗传变化和异常线粒体 关键器官如肝脏、肌细胞和肌肉的功能与 肥胖和糖尿病。因此，我们假设先入为主地接触DEHP，类似于 妊娠期暴露，通过改变后代的代谢表型而导致异常 卵母细胞的表观遗传学特征和/或线粒体功能。因此，我们建议 以下具体目标：目标1将确定先入为主的生物学暴露 相应剂量的DEHP会导致与妊娠暴露相似的后代表型。目标 2将确定两种不同暴露的分子和细胞机制 WINDOWS导致后代的代谢表型相似或不同。我们将分析 卵母细胞中RNA-seq转录组和ATACseq和亚硫酸氢盐-seq表观基因组。 后代体内的关键组织。然后，我们将确定DEHP对以下关键方面的影响 线粒体功能，如呼吸、ATP、ROS和形态。这证明了 环境污染物先入为主的编程原理可能改变我们的 对此类化合物的风险进行严格评估的意识。

Endocrine disruptors (EDs) are a group of molecules capable of altering normal endocrine function in animals and humans. We and others have demonstrated that in utero exposure to EDs causes obesity and abnormal glucose homeostasis in the offspring. Phthalates are an important group of EDs that are used in a diverse range of industrial applications leading to common exposure risk in humans. One major phthalate is di-(2-ethylhexyl)-phthalate (DEHP), a widely used compound for which dietary exposure (food processing, packaging) likely represents the main source of contamination for the general population. Both human and animal models show a link between phthalate exposure and the development of obesity and the metabolic syndrome. Similar to these studies, our preliminary data show that DEHP exposure through the diet in physiologically relevant doses prior to and during pregnancy and lactation alters DNA methylation in fetal liver, increases body weight in adult offspring in a sex-specific manner. It is becoming increasingly evident that the periconceptional stage also represents a window of susceptibility to environmental exposures on the offspring. While the mechanisms responsible for the transfer of metabolic memory from the oocyte to the offspring remain to be elucidated, 2 plausible possibilities are epigenetic dysregulation and abnormal mitochondria. Further, we and others have shown that epigenetic changes and abnormal mitochondrial function in key organs such as the liver, ß-cell and muscle have been linked to development of obesity and diabetes. Thus, we hypothesize that a preconception exposure to DEHP, similar to a gestational exposure, results in an abnormal metabolic phenotype in the offspring by altering either the epigenetic profile and or mitochondrial function in the oocyte. Thus we propose the following specific aims: Aim 1 will determine whether a preconception exposure to biologically relevant doses of DEHP results in a similar offspring phenotype as a gestational exposure. Aim 2 will determine the molecular and cellular mechanisms by which the two different exposure windows result in a similar or different metabolic phenotype in the offspring. We will profile the transcriptome by RNA-seq and the epigenome by ATACseq and bisulfite-seq in the oocyte and key tissues in the offspring. We will then determine the effects of DEHP on key aspects of mitochondrial function such as respiration, ATP, ROS, and morphology. The proof of the principle of preconception programming by environmental contaminants may change our awareness of critical assessment of the risk of such compounds.